Drug-eluting Stapes Prosthesis for the Prevention of Sensorineural Hearing Loss

药物洗脱镫骨假体预防感音神经性听力损失

• 批准号: 8225323
• 负责人: MICHAEL J. MCKENNA
• 金额: $ 34.66万
• 依托单位: MASSACHUSETTS EYE AND EAR INFIRMARY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8225323
• 关键词: Acquired Deafness; Action Potentials; Acute; Adverse effects; Animal Experiments; Animal Model; Animals; Auditory; Auditory Brainstem Responses; Biological Assay; Biomedical Engineering; Bone necrosis; Bone remodeling; Bypass; Cavia; Clinical Trials; Collaborations; Confocal Microscopy; Data; Development; Devices; Disease; Drug Delivery Systems; Drug Formulations; Ensure; Exhibits; Fluorescein; Fluorescence; Fluorescence Microscopy; Goals; Histologic; Human; Implant; Jaw; Kinetics; Knockout Mice; Laboratories; Labyrinth; Lead; Long-Term Effects; Measures; Membrane; Methods; Monitor; Mus; Otologic Surgical Procedures; Otosclerosis; Pathologic; Patients; Performance; Pharmaceutical Preparations; Physiological; Polymers; Prevention; Prosthesis; Research; Risedronate; Safety; Scala Tympani; Secure; Sensorineural Hearing Loss; Stapes; Techniques; Testing; Time; Tissues; Tympanic membrane; Zoledronate; biomaterial compatibility; bisphosphonate; bone; capsule; design; dosage; drug distribution; experience; hearing impairment; improved; inhibitor/antagonist; inner ear diseases; innovation; middle ear; molecular pathology; otoacoustic emission; ototoxicity; prevent; public health relevance; research study; round window; skeletal; technology development; treatment strategy

DESCRIPTION (provided by applicant): Otosclerosis is a disease of the otic capsule that is among the most common causes of acquired hearing loss. During the last fifteen years, our laboratory has focused on elucidating the molecular pathology of otosclerosis with the long-term goal of developing better forms of therapy. These studies have led us to a new and innovative treatment strategy: the inner ear delivery of bisphosphonates via a drug-eluting polymer. We have begun to develop and test a drug formulation for use in humans, and have developed an animal model to test it. Since most patients with otosclerosis receive stapes prosthesis, we will integrate the polymer into the prosthesis for intracochlear delivery. We will also integrate the polymer into a wafer for delivery via the round window membrane. The otic capsule is unique in that it normally exhibits little or no bone remodeling. Otosclerosis is characterized by an abnormal remodeling of the otic capsule. Some bisphosphonate compounds are potent inhibitors of bone remodeling, but potentially serious side effects can occur with systemic administration in humans such as inhibition of all skeletal remodeling and osteonecrosis of the jaw. Intracochlear and intratympanic administration should bypass these systemic problems and ensure that the drugs reach cochlear tissues and the otic capsule in the form and concentration desired. We have identified an animal model, the OPG-/- (knockout) mouse, which exhibits foci of active remodeling within the otic capsule, similar to otosclerosis. These mice also develop progressive hearing loss, similar to cases of advanced otosclerosis. We have shown that bisphosphonates are highly effective in halting the pathologic remodeling and hearing loss in OPG-/- mice. We will now investigate effects of direct intracochlear and intratympanic delivery of risedronate, a potent bisphosphonate. We have chosen risedronate because of its high potency and availability of a fluorescein conjugated form of the drug that allows its quantification and localization. These experiments will guide the development of a bisphosphonate formulation for inner ear delivery in humans. If successful, these studies will lead quickly to clinical trials in humans with progressive sensorineural hearing loss from cochlear otosclerosis using a bisphosphonate-eluting stapes prosthesis, an intratympanic bisphosphonate formulation, or both. The development of this technology will also be valuable for other inner ear disorders that may benefit from direct drug delivery. PUBLIC HEALTH RELEVANCE: If successful, these studies will lead directly to clinical trials in humans with progressive sensorineural hearing loss from cochlear otosclerosis using a bisphosphonate-eluting stapes prosthesis, an intratympanic bisphosphonate formulation, or both, using safe and well-established techniques of middle ear surgery. The development of this technology will also be valuable for other inner ear disorders that may benefit from direct drug delivery.

描述（由申请人提供）：耳粘病是耳囊的一种疾病，是获得听力损失的最常见原因之一。在过去的十五年中，我们的实验室集中于阐明耳效癌的分子病理，其长期目标是开发更好的治疗形式。这些研究使我们采取了一种新的创新治疗策略：双膦酸盐通过药物洗脱聚合物的内部递送。我们已经开始开发和测试一种用于人类使用的药物配方，并开发了一种动物模型来测试它。由于大多数耳鼻喉病患者都会接受stapes假体，因此我们将将聚合物整合到假体中以进行水上分娩。我们还将将聚合物集成到晶圆中，以通过圆形窗户膜递送。 OTIC胶囊的独特之处在于它通常几乎没有或没有骨头重塑。耳硬化的特征是耳囊的异常重塑。一些双膦酸盐化合物是骨重塑的有效抑制剂，但是在人类中，全身给药可能会出现严重的副作用，例如抑制所有骨骼重塑和颌骨的骨坏死。据推测和胰蛋白酶内的给药应绕过这些系统性问题，并确保该药物以所需形式和浓度的形式和浓度到达耳蜗组织和耳囊。我们已经确定了一种动物模型，OPG - / - （基因敲除）小鼠，该模型在耳囊内表现出活性重塑的焦点，类似于耳螺中的耳效癌。这些小鼠还会产生渐进的听力损失，类似于晚期耳效癌病例。我们已经表明，双膦酸盐在停止OPG - / - 小鼠的病理重塑和听力损失方面非常有效。现在，我们将研究直接的双膦酸盐脑内和原胰蛋白酶内递送的影响。我们之所以选择饲养酸盐，是因为它具有高效力和荧光素共轭形式的药物的可用性，从而允许其定量和定位。这些实验将指导双膦酸盐配方的开发，以用于人类内耳的递送。如果成功的话，这些研究将迅速导致使用双膦酸盐解除stapes假体，一种内胰蛋白酶内的双膦酸盐配方或两者兼有双膦酸盐的stapes stapes proshess进行性感觉性听力损失的临床试验。该技术的开发也将对可能受益于直接药物的其他内耳疾病有价值。 公共卫生相关性：如果成功的话，这些研究将直接导致使用双膦酸盐渗透性stapes假体，一种伴随性双磷酸盐的表述，或使用安全和良好的中耳部中的安全和良好的中性耳道技术。该技术的开发也将对可能受益于直接药物的其他内耳疾病有价值。